How are biotechs addressing rare chromosome disorders?

Human beings typically have 23 pairs of chromosomes. But sometimes, in rare cases, an error during cell division can result in cells having extra or missing chromosomes, indicative of chromosomal disorders.

Often, prenatal tests are carried out to detect chromosomal abnormalities. Amniocentesis is a diagnostic procedure where the amniotic fluid that protects a fetus during pregnancy is tested for a range of disorders like Down’s syndrome, Edwards’ syndrome and Patau syndrome. However, it is only offered if there is a higher chance for a baby to have a genetic condition, as – although rare – the test is associated with a risk of miscarriage as well as the development of rhesus disease, which is also known as the haemolytic disease of the fetus and newborn (HDFN).

Of late, non-invasive prenatal testing (NIPT) has been introduced to identify trisomy 13, 18 and 21, as well as abnormalities of the X chromosome, through a blood test. NIPT is regarded to be safe, like the combined first trimester screening (CFTS), which is the conventionally used screening test.

As more accurate screening tests have been developed over the years to determine chromosomal disorders in fetuses, various clinical trials to treat these disorders are underway. In advance of Rare Chromosome Disorder Awareness Day, which is observed on June 22, let us take a look at what biopharma companies are doing to treat chromosomal disorders. 

Ultragenyx’s ongoing clinical trial for Angelman syndrome

Recently, U.S.-based company Ultragenyx was authorized a protocol amendment by the U.S. Food and Drug Administration (FDA) for its drug candidate that is being evaluated in a phase 1/2 study for Angelman syndrome. This enables the company to harmonize dose ranges in the U.S. with those being used in cohorts outside the U.S., to quicken the completion of the study. 

Angelman syndrome is a rare neurogenetic disorder caused by the simultaneous deletion of the maternal chromosome 15 – and particularly the UBE3A gene which is either missing or silenced – and inheritance of two paternal copies of it. An example of genomic imprinting, the condition is characterized by developmental delay, sleep disturbances, seizures, issues with balance and coordination and sometimes, hyperactivity.

Ultragenyx’s drug candidate GTX-102, which was granted Orphan Drug status in 2019, is an antisense oligonucleotide that is designed to inhibit the expression of the UBE3A gene. Administered via an injection into the spinal canal, GTX-102 works by reactivating the expression of the paternal UBE3A allele in neurons of the central nervous system (CNS). This has been linked to improved neurological symptoms in animal models of Angelman syndrome. 

“Agreement on the protocol amendment enables comparable dose ranges across all geographies and allows us to move forward rapidly to complete the study. We have begun working urgently to activate multiple study sites in the U.S. and plan to begin enrollment as quickly as possible,” said Scott Stromatt, senior vice president and chief medical officer of neurology clinical development at Ultragenyx. “We are eager to expand the study in the U.S. to build on the encouraging data, which demonstrate important clinical activity across multiple functional domains impacted by Angelman syndrome with an acceptable safety profile.”

According to results from last year’s interim clinical trial data, AS Change Scale evaluations – a quantitative measure of the condition – investigated the drug based on five domains – sleep, behavior, communication, gross motor, and fine motor skills. Seven out of nine trial participants showed improvement from baseline in at least 3 of 5 domains as well as in the overall score.

As Ultragenyx proceeds to expedite trials to treat Angelman syndrome, Australian company Neuren Pharmaceuticals is developing NNZ-2591, a candidate that targets neurological symptoms of the disease.

Chromosome disorders: Neuren Pharmaceuticals’ diverse pipeline

NNZ-2591, which was tested in a mouse model that resembled features of Angelman syndrome in humans, was found to have improved motor performance, anxiety levels, cognition and even nullified the risk of seizures, during the course of weeks.

Currently in phase 2 clinical trials, the candidate is being evaluated in parallel with three other rare chromosome disorders, namely, Phelan-McDermid Syndrome, Pitt Hopkins Syndrome and Prader-Willi Syndrome.

Phelan-McDermid Syndrome, a genetic disorder where part of chromosome 22 is deleted – therefore, also called 22q13 deletion syndrome – and occasionally associated with a defective SHANK3 gene, causes developmental delay, and speech impairment, and patients tend to be on the autism spectrum. Moreover, 40% of people with Phelan-McDermid Syndrome develop seizures which can range from mild to severe.

For the treatment of its symptoms, Neuren Pharmaceuticals’ NNZ-2591 clinical studies not only saw that symptoms were mitigated in a mice model but also observed a stark reduction – 83% – in seizure risk, a significant therapeutic advancement. Furthermore, the altered length of dendrite spines in the brain and the hyperactivity of the ERK protein – both features associated with the disease – were brought into line during treatment.

The candidate also received the green light from the FDA to commence phase 2 trials for the treatment of Prader-Willi Syndrome, a condition brought about by the absence of genetic material in chromosome 15.

Targeting rare chromosome disorders by managing symptoms

Meanwhile, Danish multinational healthcare company Novo Nordisk, is also a key player in rare chromosome disease research.

Turner syndrome is a disorder that arises from the presence of only one X chromosome, instead of two. Affecting one in 2000 females born, the condition is associated with shortness in height, underdeveloped ovaries and an elevated risk of infertility.

The short stature is due to the inactive or deleted SHOX gene. To target this, Novo Nordisk’s Norditropin is a standard growth hormone therapy that was approved decades ago. And now, the company’s drug candidate Somapacitan is under development as well. Delivered subcutaneously, Somapacitan is a replacement of endogenous growth hormone (GH) that targets the somatotropin receptor in adults with growth hormone deficiency (GHD). Apart from Turner syndrome, for which it is in phase 3 trials at present, it is also being investigated to treat other growth disorders such as Noonan Syndrome and idiopathic short stature. 

Besides addressing growth, to prompt puberty and ensure healthy sexual development, estrogen and progesterone replacement therapies are current treatment measures that battle symptoms of Turner syndrome.

Other rare chromosome disorders like Patau syndrome, Edwards’ syndrome and Williams syndrome, although have neither cures nor targeted therapies, specific symptoms of the conditions are addressed by the healthcare sector. For instance, for Edwards’ syndrome, characterized by an extra chromosome in the 18th pair, physiotherapy is an established treatment measure to boost development. For babies who experience difficulty swallowing due to a floppy airway and poor coordination, and sometimes because of the presence of a cleft palate, feeding tubes help ease the problem.

For Williams syndrome, caused by the spontaneous deletion of genetic material from chromosome 7, like with Edwards’ syndrome, managing symptoms is key. Cardiovascular issues are handled through frequent screening visits and in some cases people are prescribed beta blockers to control hypertension, although about 20% of people with Williams syndrome undergo surgery.

As attempts to improve the quality of life for those affected by rare chromosome disorders are being made, cures for these conditions may seem far-fetched at the moment. However, with rapid technological progression, as in the case of artificial intelligence heading drug discovery now, it is not unthinkable.